This project will adapt the azide-alkyne cycloaddition reaction and related processes for use in the assembly of inhibitors of HIV protease, taking advantage of the dimeric structure of the enzyme, in two approaches. 1) Structures related to those possessing binding affinity for HIV protease will be functionalized with azide and alkyne groups. The assembly of these components into compounds with potential dual-site binding capability will be conducted in parallel combinatorial fashion both in the presence of the enzyme (the 'in situ' approach) and in standard combinatorial fashion. Both functional and alternative screens will be employed to identify leads, the latter employing new mass spectrometric techniques developed in our laboratories. (2) In-situ assembly will be used to rapidly develop inhibitors of protease mutants that have evolved to counter drug therapy.